Dr. Anderson is a physician-scientist who has a career focus on the molecular mechanisms of cerebral cortex development, as well as clinical and research expertise in schizophrenia. Continued salary support under the Research Career Award mechanism will be crucial to his career development. The cerebral cortex contains two types of neurons, excitatory projection neurons and inhibitory interneurons. Based on chemical, physiological and morphological criteria, the inhibitory interneurons occur in distinct subtypes that subserve distinct functions. Several common illnesses, including epilepsy and schizophrenia may involve the abnormal development and/or dysfunction of particular interneuron subtypes. Recent studies have determined that most cortical interneurons derive from the ventral forebrain, in the anlage of the basal ganglia. The long-term objective of this research is to understand the molecular basis for cortical interneuron subtype specification. Aim 1: Regional and temporal influences on interneuron subtype specification. Two methods will be employed to examine whether distinct interneuron subtypes have distinct sources. First, cells from various cortical and subcortical regions of mouse telencephali, at various times over the age-range of cortical neurogenesis, will be transplanted into neonatal cortical environments in vivo and in vitro. The effect of the donor cell's place and time of birth on their differentiated fate will be assessed. Second, a transgenic mouse expressing Cre-recombinase under control of the transcription factor Nkx2.1 will be generated. This mouse will permit fate-mapping of cells that originated within a subregion of the subcortical telencephalon, the medial ganglionic eminence and preoptic area. Aims 2 and 3: The role of Sonic Hedgehog in interneuron subtype specification. Since evidence suggests that important aspects of interneuron subtype specification occur within the ventral forebrain, a candidate molecule approach is being taken to study factors which may influence this process. The primary factor being examined is Sonic Hedgehog (Shh), a glycoprotein involved in cell fate determination in the ventral spinal cord which is also expressed in the ventral forebrain. Shh's role in interneuron specification will be studied by in vitro gain and loss of function manipulations followed by transplantation of neuronal progenitors into cortical environments in vivo and in vitro. In addition Shh function will be studied using conditional knockouts that target Shh expression within the ventral forebrain.